Process for preparing 21-aldehydes of the cyclopentano polyhydrophenanthrene series



Patented Dec. 30, 1941 2,268,084 ICE PROCESS FOR PREPARING ZI-ALDEHYDES OF THE. CYCLOPENTANO POLYHYDRO- PHENANTHRENE SERIES Tadeus Reichstein, Basel, Switzerland, assignor to Roche-Organon, In ration oi. New Jersey c., Nutley, N. J., a corpo- No Drawing. Appllcatlon March 1, 1940, Serial No. 321,795. In the Netherlands April 6, 1939 11 Claims.

The present invention relates to a process for preparing 2l-aldehydes of the cyclopentano polyhydrophenanthrene series. It has been found that the desired aldehydes are obtained easily and with good yields by treating 21-halogeno compounds of the pregnane series with tertiary bases, converting the quaternary ammonium compounds with aromatic nitroso compounds and decomposition with acid of the intermediate product thus obtained.

According to one specific embodiment of the invention a-keto-aldehydes of the cyclopentano polyhydrophenanthrene series can be prepared. These a-keto-aldehydes could only diflicultly be prepared. Only Mason 8; Hoehn (Journ. Am. Chem., 60, 1493, 1938) possibly have obtained a small amount of dihydroxy-3,12-pregnanone-20- al-21 as an intermediate product, but have not recovered it in pure condition. Moreover the process applied by these investigators is hardly suitable for the preparation of a,-kcto-aldehydes of the present series containing also double bonds in the ring system. According to the invention, however, the keto-aldehydes mentioned are obtained with good yields and in a skillful manner, it being quite immaterial whether or not the ring skeleton contains double bonds, while also the nature of the substituents in the ring skeleton is immaterial for the course of the reaction in the lateralchain. q For the preparation of these a-keto-aldehydes according to the invention compounds of the cyclopentano polyhydrophenanthrene series having a lateral chain with the structure -CO.CH:- halogen which may contain also double bonds as well as different substituents in the ring skeleton, are converted with tertiary bases and the quaternary salts formed are treated with aromatic nitroso compounds, preferably in the presence of acid binding means, e. g. alkalis, alkali carbonates, amines, etc.

The intermediate products thus obtained being possibly nitrones then are decomposed with acids yielding thereby easily the desired keto-aldehydes. The course of the reaction can be elucidated in the following manner (X standing for the cyclopentano polyhydrophenanthrene nucleus and pyridine being here the tertiary base used) (R=aromatic radical, e.g. ClHs. CcHiN(CIIa)2 acid 111 XCO.CHO+RNHOH The halogeno-Zl-pregnanones used as starting material can be prepared according to applicaare already known for other types of compounds, vide e. g. Kriihnke c. s., Ben, 69, 2006 (1936); 71, 2583 (1938); '72, 527 (1939).

The particular significance 01' the new compounds prepared according to the present process which in general are very sensitive for external influences and, e. g. in the course of time alter by contact with the air, is due to the fact that they either show the physiologic properties of the hormone of the suprarenal cortex or can be converted into compounds having these properties.

A hydroxy group in the 3-position can be oxidised to a keto group, the sensitive glyoxal group in the lateral chain, if desired, may be protected by acetalysation (vide Houben, Die Methoden der' Organischen Chemie, vol. 3, page 191 a. f.,

Leipzig, 1930). The same compounds can be prepared by subjecting dibromo-4,2l-pregnanecliche-3,20 which may be obtained by brominating bromo-2l-pregnanedione-3,20 to a treatment with pyridine followed by that with aromatic nitroso compounds. The bromide atom in the nucleus is thereby split oil in the form of hydrobromic acid, while a double bond between the carbon atoms 4 and 5 is formed.

Example 1 acid (appln. Ser. No. 195,161). After allowing the reaction mixture to stand for half an hour it is evaporated till dry and the residue is re crystallised from a small amount of benzene and washed with ether. In that manner colourless crystals melting at 152-154 C. are obtained. From diluted alcohol a hydrate crystallising as small leaflets is obtained.

200 mg. of this bromo-2l-pregnenolone are dissolved in 1 cm. of heated benzene and after addition of mg. of anhydrous pyridine heated at 100 C. for half an hour. After cooling the solution is diluted with ether and the precipitated crystals are washed with ether. From the mother liquor a further quantity of these crystals can be recovered by evaporation and addition of ether. The total yield is 200 mg. of a colourless crystal powder melting under decomposition at approximately 300 C. The substance is difllcultly soluble in water and somewhat more easily soluble in alcohol and soluble in ether.

tion Serial No. 195,161. Analogous conversions The 200 mg. of pyridinium salt are dissolved in 25 cm. of alcohol under heating. Aftercooling 62.3 mg. of p-nitrosc-dimethyl-aniline are added which dissolve by shaking. Thereupon the mixture is cooled down to 5 C. after which 0.42 cm} of a normal sodium hydroxide solution is added whereby the green colour soon turnsito red. After addition of some water the'alcohol; is removed completely in vacuum at room tempera- I tures Thereby a red resin precipitates, which is removed by shaking out with ether. The ether solution is washed with a small amount of water This nitron thus obtained from'the orange-yel- "low crystal mass was immediately treated furand then shaken energetically with cm. of sul- 1 is dried and strongly thickened. After some time crystals separate out, which are washed" with ther for whichpurpose it was shaken with ether and diluted hydrochloric acid in a separatory funnel. The ethereal solution was still shaken three times with 2-N hydrochloric acid and after that washed with water. a solution of potassium ether and a very small amount of benzene. They melt at 143-144 C. and after dissolving in a small amount of methanol they reduce very strongly an alkaline solution of silverdiamine. By evaporation of the mother liquor a further quantity of crystals is obtained which, however, shows a less sharp melting point. It is possible to obtain the substance in entirely pure condition by sublimation in a high vacuum and/orby chromatographic Example 2- I ethereal solution is washed with a small quantity of a solution of potassium bicarbonate and dried with potassium carbonate. Thereupon the ether is evaporated and the residue is dissolved in 5 omfiof dry benzene. Now 0.8 g. of tertiary aluminium butylate and 1.5 cm. of acetone are added and the-mixture'is boiled during 6 hours at a reflux condenser with exclusion of moisture. After cooling ether is added and a solution is shaken with I water and diluted sulphuric acid whereby the reaction product goes into the ether layer. This layer is still washed with diluted sulphuric acid and water, dried and evaporated, whereupon the residue is purified by sublimation in a high vacuum, chromatographic adsorption and/or crystallisation, etc. The pregnene-4-dione-3,20-al-21 shows a very strong cortin action in the animal test.

Example 3 Preparation of pregnene-4-dione 3,20-al 21 from chloro-21-prog'esterone.

1 g. chloro-21-progesterone was heated for one hour with 10 cm. of dry pyridine on a water bath with exclusion of moisture. After addition of 10 cm. of benzene the mixture was cooled and after two hours the crystals which had separatedout were filtered oil by suction and washed with benzene. The yield was 1.042 g. of colourless crystals melting at 274275 C. (corn) under decomposition. The product is easily soluble in water and alcohol and difilcultly soluble in benzene and ether. 214 mg. of this pyridinium chloride were dissolved in 6.7 cm. of alcohol after which 75 mg. of nitroso-dimethyl aniline were added.

After cooling down to 10 C." 0.5 cm. of a 1-H sodium hydroxide solution was added whereby the colour changed into brown-orange. After 5 minutes 4 cm. of water were added under further bicarbonate and water, dried and concentrated till the crystallisation started. The first crystal fraction after decanting and washing with ether Weighed approximately mg. and showed a melting point of 104106 C. From the mother liquor were obtained still 60 mg. of crystals having a somewhat lower melting point. Since the product can be recrystallised only diiiicultly. it was possible that it was not entirely pure yet. According to the analysis it was a monohydrate. By conversion into the dimethylacetal with hydrochloric acid in methanol the same product can be obtained which is obtained by oxidation of the dimethylacetal of pregnene-5-ol-3-one-20-- al-21 showing a melting point of 86-89 C. :A

mixture of acetals prepared in both manners showed no depression of the melting point. The same dimethylacetal was also obtained from the products separated from the mother liquor, which crystallised diflicultly. For further characterising the. trioxime showing a melting point of 160-170" C. and the osazone showing a melting point of 175-177 C. were prepared.

According to another specific embodiment of the invention a-fi-unsaturated aldehydes of the cyclopentano polyhydrophenanthrene series can be prepared in an excellent manner. These a-flunsaturated aldehydes are known from the paper the mother liquor still a small quantity of nitron could be recovered by shaking out with ether.

Acta, 22, 894). These investigators have prepared these compounds by oxidation of the corresponding unsaturated alcohols, which according to Ruzicka and Miiller (Helv. Chim. Acta, 22, 416, 1939) were obtained from the corresponding hal-' ogen compounds by conversion with salts. e. g. acetates, and saponification of the esters formed.

According to the invention, however, it is possible to convert these o e-unsaturated halogen compounds of the cyclopentano polyhydrophenanthrene series, which contain the group C CH-CHr-halogen in the molecule in a simple manner and with excellent yields into the corresponding aldehydes. A further advantage is that the a-fl-unsaturated halogen compounds which have to be used as a starting material can be used in many cases in impure condition since the quaternary ammonium compounds crys tallise in the presence of the tertiary base used.

The impurities which do not form quaternary ammonium compounds, are easily removed in that manner.

Example 4 Preparation of pregnadiene-4,17-one-3-al-2l.

(a) Pyridinium compound of bromo-21-preg-- nadiene-4,17-one-3.

2 cm. of dry pyridene were added to the crude bromo-21-pregnadiene-4,17-one-3, which was obtained from 400 mg. of vinyltestosterone in the form of a colourless syrup according to the prescription of Ruzicka and Miiller. Already after 1 minute the white crystals separated out. The next day the mixture was diluted with dry benzene, the precipitate was filtered oh by suction and washed with benzene. The product thus obtained had a melting point of 214 C. and the yield was 300 mg., i. e. 52% expressed as'a per centage of the vinyltestosterone. Neither after I 2,2os,oa4

evaporation and renewed addition of pyridine and later benzene, nor even by inoccuiating, the mother liquor did yield further crystals so that the relatively low yield in this case is exclusively due to the impurity of the starting material used. That the starting material was impure was also rendered possible by the fact that it could not be induced to crystallisation, though Ruzicka and Miiller indicate that the product crystallises well. (1. page 420). In a second experiment a yield of 51% expressed as a percentage of the vinyltestosterone was obtained.

(b) Nitron from pyridinium compound.

228 mg. of pyridinium bromide millimol.)

were dissolved in a mixture of 1 cm. of water and 6 cm. of ethanol after which 75 mg. of p-nitroso-dimethylaniline were added. The solution was immediately cooled with iceand salt and under shaking 0.3 cm. of 0.1-N sodium hydroxide solution were added. The colour of the solution did not alter. After the mixture had been brought at room temperature after an hour, however, the solution obtained'gradually a reddish brown colour. After having been kept two hours" at room temperature 2 cm? of water were added, after which the slightly turbid solution was. kept two days in the refrigerating room. Thereby yellow-brown crystals had formed which after being filtered oil by suction were washed water, whereby the ether solution became nearly colourless. After drying with sodium sulphate the solution was strongly concentrated and the crystallisation was promoted by addition of pentaneh The crystals obtained were washeg with pentane. The mother liquor yielded also 'a' quantity of crystals. After recrystallisation from acetone-water the melting point was 146-152 0. (corn) and the yield was 56 mg. (appr. 100%) pregnadiene-4,17-one-3-al-21. In a similar manner the aldehyde could be obtained from the mother liquor of the preparation of the nitron. The substance strongly reduces an ammonical silver solution, i. e. the change of the colour to black takes place after 1-2 minutes.

In a second experiment the nitron was not purified previously, but was treated immediate- 1y with hydrochloric acid. The crude aldehyde was purified chromatographically, whereby a yield of aldehyde of approximately 60% expressed as a percentage of the pyridinium bromide was obtained.

Example 5 Preparation of acetoxy-3-pregnadiene-5,1'l-al- 21.

According to the prescription of Ruziclra and Miiller acetoxy-S-pregnadlene-tSJO-ol-l'l was treated with phosphor tribromide, however in the-presence of an excess oi pyridine. Thereby the pyridinium compound of bromo-21-acetoxy- 3-pregnadiene-5,17 was formed immediately. The reaction was carried through without separation of the nitron.

40 a saturated solution of potassium carbonate and To the solution of 125 76 mg. of pyridinium-bromide in 2.5 0111. of alcohol were added at room temperature 38 mg. of pnitroso-dimethylaniline and 0.25 cm. of a l-N sodium hydroxide solution. After standing for 5 three hours the solution was rinsed into a separatory funnel, mixed with 50 cm. of ether and cm. of 2-N hydrochloric acid and well shaken. After addition of water the ether solution was separated, still washed twice with hydrochloric I m acid and thereupon with water, bicarbonate solution and water, dried and evaporated. 'The residue of 82 mg. of crystals was acetylated for 17 hours at room temperature with 2' cm. of pyridine and 0.6 cm.' of acetic acid anhydride. After evaporation, addition of ether, washing, drying and evaporation 90 mg. of brown coloured crystals showing a melting point of 179-190 C. were obtained. These crystals were Sublimated in vacuum and thereupon recrystallised from ace- 20 tone-water, whereby white needles showing a melting point of 175-183 C. were obtained. The yield expressed as a percentage of the pyridinium bromide was approximately 90%.

, According to the invention also pregnenediones- 3,20-al-21 can bepreparedfromhalogeno-2l-pregnenediones, efg. pregnene-4-dione 3,20 a1 21 from halogeno-2l-pregnene-4 dione -3,20. The V halogeno-2l-pregnenediones used thereby as a starting material can be prepared from the corresponding halogeno-Z1-pregnenol-3-ones-20 by transformation of the hydroxyl group attached to C: to a keto group by dehydrogenation by reaction with a carbonyl compound in the presence of a metal-or a halogenometal alcoholate.

Various changes may be made in the details disclosed in the foregoing specification without departing from the invention or sacrificing the advantages thereof.

I claim:

l. A method for preparing 21-aldehydes of the cyclopentano polyhydrophenanthrene series, comprising treatment of 2l-halogeno compounds of the pregnane series with tertiary bases, conversion of the quaternary ammonium compounds formed with aromatic nitroso compounds and decomposition with acid of the mtermediataprodnot obtained.

2. A method for preparing 2l-aldehydes of the cyclopentano polyhydrophenanthrene series, comprising treatment of 2l-halogeno compounds of the pregnane series with tertiary bases, conversion of the quaternary ammonium compounds formed with aromatic nitroso compounds in the presence of acid binding means and decomposition with acid of the intermediate product obtained.

3. A method for preparing a-keto-aldehydes of the cyclopentano polyhydrophenanthrene series, comprising treatment of compounds of the preggo nane series having a lateral chain with the structure -CO.CHz-halogen with tertiary bases, conversion of the quaternary ammonium compounds formed with aromatic nitroso compounds and decompositon with acid of the intermediate prodas ucts obtained.

4. A method for preparing a-keto-aldehydes of the cyclopentano polyhydrophenanthrene series. comprising treatment or nuclearly unsaturated compounds of the pregnane series having 9. lat-- 7o eral chain with the structure CO.CHz-halogen with tertiary bases, conversion of the quaternary ammonium compounds formed with aromatic nitroso compounds and decomposition with acid of the intermediate products obtained.

5. A method for preparing a-keto-aldehydes of the cyclopentano polyhydrophenanthrene series, comprising treatment with tertiary bases of compounds or the pregnane series having a lateral chain with the structure C O.CHz-halogen and inv the Ca position substituents selected'trom the class consisting of hydroxyl groups, ketonic oxygen groups and group'saeadfly converted thereto, conversion of the quaternary ammonium compounds formed with aromatic nitroso compounds and decomposition with acid oi the intermediate products obtained.

8. A method for preparing a-keto-aidehydes oi the cyclopentano poiyhydrophenanthrene series, comprising treatment of a halogeno-21-pregnene- 5-ol-3-one-20 with tertiary bases, conversion of the quaternary ammonium compounds formed with aromatic nitroso compounds and decomposition with acid of the intermediate products obtained.

7. A- method for preparing a-keto-aidehydes oi the cyclopentano poiyhydrophenanthrene series, comprising treatment 01' a ha1ogeno-21-pregnene- 5-o1-3-one-20 with tertiary bases, conversion of the quaternary ammonium compounds iormed with aromatic nitroso compounds, decomposition with acid of the intermediate products obtained and oxidation of the pregnene-5-ol-3-one-20-al- 21 to pregnene-4-dione-3,20-ai-21.

8. Amethod tor preparing m-keto-aldehydes oi the cyciopentano polyhydrophenanthrene series, comprising treatment or a ha1ogeno-21-pregnene- 5-o1-3-one-20 with tertiary bases, conversion of the quaternary ammonium compounds formed with aromatic nitroso compounds, decomposition with acid of the intermediate products obtained and oxidation oi the pregnene-5-oi-3-one-20-ai- 21 to p mene-4-dione-3,20-ai-21 under temporary protection of the aldehyde group.

9. A method for preparing a-p-unsaturated aidehydes or the cyciopentano polyhydrophenanthrene series, comprising treatment of compounds or the pregnane series containing the group C=CH.CHz-halogen with tertiary bases, conversion of the quaternary ammonium compounds formed with aromatic nitroso compounds and decomposition with acid oi' the intermediate productobtained.

10. A method for preparing pregnadiene-4,17- one-3-al-21, comprising treatment of halogeno- 2i-pregnadiene-4J7-one-3 with a tertiary base, conversion of the quaternary ammonium comcomposition with acid-oi the intermediate product obtained.-

TADEUS REICHSTEIN. 

